Pyrrole-imidazole polyamide targeted to break fusion sites in TMPRSS2 and ERG gene fusion represses prostate tumor growth

Abstract

Aberrant overexpression of ERG induced by the TMPRSS2-ERG gene fusion is likely involved in the development of prostate cancer. Synthetic pyrrole-imidazole (PI) polyamides recognize and attach to the minor groove of DNA with high affinity and specificity. In the present study, we designed a PI polyamide targeting TMPRSS2-ERG translocation breakpoints and assessed its effect on human prostate cancer cells. Our study identified that this PI polyamide repressed the cell and tumor growth of androgen-sensitive LNCaP prostate cancer cells. Targeting of these breakpoint sequences by PI polyamides could be a novel approach for the treatment of prostate cancer. Recurrent fusions of TMPRSS2 with members of the E26 transformation-specific (ETS) family of transcription factors were found in prostate cancer tissues, and correlation with poor prognosis. This study is the first report that the fusion transcripts were repressed by a synthetic PI polyamide, which can be a new therapeutic intervention for prostate cancer.